Department of Neurology, Klinikum Grosshadern, University of Munich, Germany.

4

Biospective Inc., Montréal, QC, Canada.

5

McGill University, Montréal, QC, Canada.

Abstract

In this work, we propose a diffusion MRI protocol for mining Parkinson's disease diffusion MRI datasets and recover robust disease-specific biomarkers. Using advanced high angular resolution diffusion imaging (HARDI) crossing fiber modeling and tractography robust to partial volume effects, we automatically dissected 50 white matter (WM) fascicles. These fascicles connect deep nuclei (thalamus, putamen, pallidum) to different cortical functional areas (associative, motor, sensorimotor, limbic), basal forebrain and substantia nigra. Then, among these 50 candidate WM fascicles, only the ones that passed a test-retest reproducibility procedure qualified for further tractometry analysis. Leveraging the unique 2-timepoints test-retest Parkinson's Progression Markers Initiative (PPMI) dataset of over 600 subjects, we found statistically significant differences in tract profiles along the subcortico-cortical pathways between Parkinson's disease patients and healthy controls. In particular, significant increases in FA, apparent fiber density, tract-density and generalized FA were detected in some locations of the nigro-subthalamo-putaminal-thalamo-cortical pathway. This connection is one of the major motor circuits balancing the coordination of motor output. Detailed and quantifiable knowledge on WM fascicles in these areas is thus essential to improve the quality and outcome of Deep Brain Stimulation, and to target new WM locations for investigation.

Important steps of our processing pipeline illustrated on the corticospinal tract (CST). a) Raw dMRI images are processed. b) Whole brain deterministic tractography is performed. c) WM fascicles are extracted (CG in red, CST in blue, IFOF in green, SLF1 in yellow, UF in turquoise). d) Fascicles are processed independently (CST shown). e) Outliers are removed. f) Centroids are extracted. g) The fascicle is subsampled in 20 equidistant parts (colored independently). h) Tract profiles are computed (with standard deviation in gray). Note: In this example, the outlier removal threshold was slightly exaggerated in order to visually show its effect. In practice, the CST was not affected by the outlier removal. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Comparison of the FA tract profile of the corticospinal tract (CST) and fascicle #2, described in , from three different acquisitions: the first two from the same subject and the last one from a different subject. In (a), we have the desired case where the two intrasubject acquisitions are closer to each other than to the other subject's acquisitions, while in (b) we have the unfortunate case of the subject's first acquisition being closer to the other subject's acquisition than its second acquisition. (For interpretation of the references to color in this figure, the reader is referred to the web version of this article.)

To extract specific WM fascicles, specific regions were segmented using an atlas, illustrated in (a) sagittal and (b) coronal view: , , , , and . Some fascicles extracted also connected various regions of the cortex which are illustrated in (c): , , , , and . (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Some of the 20 specifically extracted WM fascicles in blue, named in . In (a), we have the fascicles connecting the cortex (fascicles #’s 1, 2, 3 and 18). In (b), we have the fascicles connecting the cortex (fascicles #’s 4, 5, 6 and 19). In (c), we have the fascicles connecting the cortex (fascicles #’s 7, 8, 9 and 20). Then, in the second row, we have the four fascicles connecting the (fascicles #’s 14 to 17). Fascicles #’s 10 to 13 are not shown because they were too short for proper visualization. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Our test-retest scores on our healthy dataset. In (a), the overlap of two CST from different subjects (in red and blue) are shown. Dice coefficient measures the overlap in purple. In (b), the average fascicle weighted Dice coefficient across all intrasubject and in (c) the average difference between the inter and intrasubject FA tract profile distance are plotted. The red line is the minimum value measured across all fascicles. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Our test-retest scores on the PPMI dataset. In (a), the average fascicle weighted Dice coefficient across all intrasubject and in (b) the average difference between the inter and intrasubject FA tract profile distance. The red line is the chosen threshold measured from the test-retest dataset in . Fascicles #1 to 20 refer to the fascicles introduced in . The bolded fascicles are the ones that are above both thresholds and therefore passed our test-retest assessment. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Heatmap of p-values projected on different pathways of a specific subject. Yellow to red signifies higher metric values in PD subjects than controls, red values being the most significant (p-value very close to a perfect 0). Green to pink signifies lower metric values in PD subjects than controls, pink values being the most significant (p-value very close to a perfect 0). For the CC, the left of the figure signifies the left side of the patient. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)